xevinapant (Debio 1143) / Debiopharm, Ascenta, Ascentage Pharma, EMD Serono - LARVOL DELTA

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (SNO 2025) - "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival (SABCS 2025) - " 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (WFNOS 2025) - P | "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor

Sox9-iCaspase9 Mouse Model for Inducible Ureteric Bud Ablation to Generate Chimeric Scaffolds for Kidney Regeneration (KIDNEY WEEK 2025) - "AP20187 and AT406 were daily added to the culture medium to eliminate Sox9-positive cells...This approach could be crucial for overcoming species-specific barriers in the generation of kidney chimeras. This Sox9-iC9 mouse model is a promising platform for these critical next steps."

Preclinical • SOX9

In vitro-in vivo extrapolation of intrinsic clearance based on data from human hepatocyte spheroids - A case study with the low-clearance drug xevinapant. (PubMed, Xenobiotica) - "The remaining clearance is renal (∼20%) and metabolic, but potentially extrahepatic (∼50%).4. This research highlights the importance and benefits of utilizing advanced in vitro techniques, such as human hepatocyte spheroids, to accurately characterize drug metabolism, providing valuable insights for pharmacokinetic evaluations and, ultimately, supporting the development of a PBPK model and understanding the DDI risk of xevinapant."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor

Green and sustainable synthesis of antimicrobial silver nanoparticles from cold-pressed bitter almond oil residue. (PubMed, Bioorg Chem) - "Phytochemical analysis showed REE was rich in chlorogenic acid (45.19 %) and quercetin (31.73 %), while RSS contained a higher quercetin concentration (88.34 %). Nanoparticle formation was confirmed by UV-Vis spectroscopy, showing surface plasmon resonance at 406.5 nm (REE-AgNPs) and 410 nm (RSS-AgNPs)...These results highlight bitter almond residues as valuable, eco-friendly resources for green nanoparticle synthesis. The study contributes to advancing bioeconomy strategies and developing sustainable nanotechnologies for environmental and biomedical applications."

Journal

Xevinapant plus chemoradiotherapy negatively sculpts the tumour immune microenvironment in head and neck cancer. (PubMed, Cancer Res Commun) - "Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • NR4A3

BONE METABOLIC DISORDERS AS THE FIRST MANIFESTATION OF AUTOIMMUNE ENTEROPATHIES (UEGW 2025) - "Laboratory abnormalities included CRP at 6.78 mg/L, fecal calprotectin >1000 μg/g, total IgA at 1.91 g/L, and Anti-tTG IgA at 406.1 RU/mL...The therapeutic approach was tailored to the patient's condition: biological therapy (Infliximab), a gluten-free diet, bisphosphonates, calcium, and vitamin D supplementation. Both Crohn's and Celiac disease are primarily considered gastrointestinal (GI) disorders, but they are systemic conditions that may present with a broad range of extraintestinal manifestations. Both Crohn's and Celiac disease are primarily considered gastrointestinal (GI) disorders, but they are systemic conditions that may present with a broad range of extraintestinal manifestations. These may develop earlier than, or in the absence of, classic GI symptoms and may be the only indication of the underlying condition. Patients presenting with osteopenia, osteoporosis, or fractures may initially be evaluated for metabolic bone disorders, while..."

Back Pain • Celiac Disease • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Lumbar Back Pain • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoporosis • Pruritus • Rheumatology

Anticandidal activity of greenly synthesized silver nanoparticles formulated using Alkanna tinctoria roots against multidrug resistant candidal pathogens. (PubMed, Sci Rep) - "Characterization confirmed spherical At-AgNPs with 19.91 nm diameter by TEM and 120.6 nm hydrodynamic size, exhibiting a UV-Vis peak at 406.27 nm...SEM imaging revealed extensive morphological damage to fungal cells following combination treatment. These results position At-AgNPs as a viable adjunct therapy capable of boosting conventional treatment effectiveness while potentially lowering required drug doses and minimizing side effects in resistant Candida infections."

Journal • Candidiasis • Infectious Disease

Synthesis of the 1,5-Diazabicyclo[6.3.0]dodecane Core Structure of Xevinapant. (PubMed, J Org Chem) - "1,5-Diazabicyclo[6.3.0]dodecanone amino acid scaffold serves as an important scaffold for developing SMAC mimetics, including clinical candidates like Xevinapant and Dasminapant. Herein, we report a novel, efficient, and potentially scalable synthesis of the core structure of Xevinapant achieved in 7 steps from a pyroglutamic acid derivative, with an overall yield of 8.4%, facilitating further development of IAP inhibitors."

Journal • Oncology

Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study. (PubMed, J Clin Oncol) - "Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN."

Clinical • Journal • P3 data • Head and Neck Cancer • Hematological Disorders • Neutropenia • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Innovative first-order UV and fluorescence spectroscopic methods for the quantification of rufinamide in the presence of its toxic degradant: Application of AGREE tool. (PubMed, Spectrochim Acta A Mol Biomol Spectrosc) - "The RUF's fluorescence and the oxidative degradant (OXD) emission appeared at 406 and 426 nm, following the excitation at 373 and 368 nm respectively. The limit of quantitation (LOQ) values were of 0.14 and 0.27 μg mL-1, while the limit of detection (LOD) values were 8.19 and 0.41 μg mL-1 for spectrophotometric and spectrofluorometric methods respectively. AGREE and analytical eco-scale was two of the tools used to assess and approve the proposed method's greenness."

Journal • CNS Disorders • Epilepsy

The reprogramming impact of SMAC-mimetic on glioblastoma stem cells and the immune tumor microenvironment evolution. (PubMed, J Exp Clin Cancer Res) - "In summary, Xevinapant exhibits robust anti-tumor activity on GSCs and favorable immune modulation of the TME in GBM, hence providing a rationale for further clinical investigation in GBM."

Biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Immune Modulation • Immunology • Oncology • Solid Tumor

Erythrocytosis as an indicator of disease progression of small cell lung cancer: A case report. (PubMed, Respir Med Case Rep) - "The patient underwent stereotactic radiosurgery (SRS) and received four cycles of combination therapy with cisplatin, etoposide, and durvalumab, followed by maintenance therapy with durvalumab to achieve disease control...Concurrently, new brain metastatic lesions were identified, and serum erythropoietin (EPO) levels were markedly elevated at 406 mIU/mL...Notably, WBRT appeared to contribute to the normalization of serum EPO levels and resolution of polycythemia. This report elucidates the clinical course and relevance of this condition based on a literature review."

Journal • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

XXL_2022-01: Study Comparing RT With Cetuximab + Xevinapant to RT With Cetuximab-placebo in Patients With Head and Neck Cancer (clinicaltrials.gov) - P3 | N=19 | Terminated | Sponsor: Groupe Oncologie Radiotherapie Tete et Cou | Trial completion date: Mar 2025 ➔ Sep 2024 | Completed ➔ Terminated; toxicity

Trial completion date • Trial termination • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

XXL_2022-01: Study Comparing RT With Cetuximab + Xevinapant to RT With Cetuximab-placebo in Patients With Head and Neck Cancer (clinicaltrials.gov) - P3 | N=19 | Completed | Sponsor: Groupe Oncologie Radiotherapie Tete et Cou | Suspended ➔ Completed | Trial completion date: Oct 2035 ➔ Mar 2025 | Trial primary completion date: Oct 2025 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Xevinapant plus avelumab in advanced solid tumours, with a dose expansion in advanced non-small-cell lung cancer: exploratory biomarker, safety and efficacy analyses from an open-label, nonrandomised phase Ib study. (PubMed, Ther Adv Med Oncol) - P1 | "NCT03270176 (https://clinicaltrials.gov/study/NCT03270176). Registered on ClinicalTrials.gov on 29 August 2017."

Biomarker • IO biomarker • Journal • P1 data • Fatigue • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • IL10 • IL13 • IL1B

Radio-sensitizing activity in apoptosis pathway in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) (AACR 2025) - "This study evaluates the efficacy of the IAP inhibitor AT406, alone and with radiation, in both HPV positive (UM-SCC47 and UD-SCC2) and HPV-negative (Cal27 and DET562) HNSCC cell lines...In addition, Liquid Chromatography- Mass Spectrometry (LC-MS/MS) is being utilized to profile changes in protein expression under different treatment conditions to identify molecular contributors to resistance mechanisms. These studies aim to provide mechanistic insights into IAP inhibition and inform the development of combination therapies outcomes in HNSCC."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BIRC3 • CASP3 • CASP7 • XIAP

Additional Mechanism of Xevinapant as Agonist of Bitter Taste Receptor T2R14 in Head and Neck Squamous Cell Carcinoma (COSM 2025) - "Given that T2R14 is expressed both intracellularly and extracellularly, new therapeutic strategies for xevinapant could include topical or injectable formulations targeting T2R pathways. Additionally, T2R-mediated off-target effects of xevinapant should be considered in evaluating drug toxicity, as T2Rs are expressed in various normal tissues outside of the oral cavity."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Quantitative Analysis of Aspirin, Telmisartan, and Bisoprolol in Spiked Human Plasma Using Green Spectrofluorimetric Analysis. (PubMed, Luminescence) - "However, direct fluorescence detection of aspirin and telmisartan proved challenging because their native emission spectra at 406 and 375 nm overlapped. The method's greenness was further evaluated using the Green Analytical Procedure Index and the Analytical GREEnness metrics. The results showed that the employed procedure was environmentally friendly."

Journal

Additional Mechanism of Xevinapant as Agonist of Bitter Taste Receptor T2R14 in Head and Neck Squamous Cell Carcinoma (AHNS-COSM 2025) - "Given that T2R14 is expressed both intracellularly and extracellularly, new therapeutic strategies for xevinapant could include topical or injectable formulations targeting T2R pathways. Additionally, T2R-mediated off-target effects of xevinapant should be considered in evaluating drug toxicity, as T2Rs are expressed in various normal tissues outside of the oral cavity."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Cerebral Polyopia Due To Paraneoplastic Monoclonal IgG4-Related Hypertrophic Pachymeningitis (AAN 2025) - "IgG4 was elevated at 406 mg/dL (normal <86 mg/dL)...For presumed IgG4-mediated hypertrophic pachymeningitis, she received three days of 1 gram IV methylprednisolone followed by a 6-week prednisone taper...This patient presented with cerebral polyopia that ultimately resulted in a diagnosis of paraneoplastic monoclonal IgG4-RD associated with SCLC. This case is the first known association between SCLC and IgG4-RD. Treatment with corticosteroids led to clinical and radiographical improvement, reinforcing their utility in atypical cases."

Cardiovascular • CNS Disorders • Epilepsy • Immunology • Infectious Disease • Lung Cancer • Migraine • Mood Disorders • Oncology • Ophthalmology • Pain • Sjogren's Syndrome • Small Cell Lung Cancer • Solid Tumor

FDA grants Orphan Drug Designation to Debiopharm International SA’s IAP inhibitor Debio 1143 in the treatment of ovarian cancer (Debiopharm Press Release) - "Debiopharm International SA (Debiopharm), a Swiss-based company, part of Debiopharm Group™, today announced that the FDA Office of Orphan Products Development (OOPD) has granted Orphan Drug Designation to Debio 1143 for treatment of Ovarian Cancer."

Orphan drug • Ovarian Cancer

Facile preparation of a hydrophilic Eu-based ratiometric fluorescent nanosensor for Cu2+ ion detection and imaging in living cells. (PubMed, Anal Methods) - "PAAC-Eu was easy to disperse in aqueous media and exhibited two characteristic emission bands at 406 nm and 618 nm, respectively, upon excitation at 350 nm...Moreover, a portable paper-based sensor was developed by loading PAAC-Eu in filter paper, which could enable visual detection of Cu2+ ions without using large instruments. Finally, cell experiments demonstrated the low cytotoxicity and good cell permeability of PAAC-Eu, and ratiometric fluorescence imaging of Cu2+ ions in living cells was successfully performed."

Journal

EMA grants Orphan Drug Designation to Debiopharm International SA’s IAP inhibitor Debio 1143 in the treatment of Ovarian Cancer (Debiopharm Press Release) - "Debiopharm International SA (Debiopharm), part of Debiopharm Group™, a Swiss-based global biopharmaceutical company, today announced that the European Medicines Agency (EMA) granted Orphan Drug Designation to Debio 1143 for treatment of Ovarian Cancer affecting around 154 000 people in the European Union (EU)."

Orphan drug • Ovarian Cancer